The present invention relates to a novel process for the reduction of alkyne compounds; in particular, the invention relates to a process for the preparation of cyclohexene derivatives which are suitable as intermediates for the preparation of carotinoids.
A large number of the industrial carotinoid syntheses described in the literature, including the preparation of astaxanthine, proceed via cyclohexene intermediates which, in additon to one or more Cxe2x95x90C double bonds, also contain a Cxe2x95x90C triple bond. To form a conjugated double bond system, this triple bond has to be partially reduced in a separate process step.
In the case of the alkynediol IVa involved in the astaxanthine synthesis described in DE-A-43 22 277, this can be done with zinc/acetic acid in methylene chloride. 
EP-A-0 005 748 relates to another process for the preparation of astaxanthine, in which the partial reduction of the alkynediol of formula IIIa is likewise carried out with zinc/acetic acid in methylene chloride. 
The disadvantage of the zinc/acetic acid reduction described is the inadequate selectivity of the method. Unwanted by-products, e.g. the formation of spiro compounds which cannot be converted to the desired secondary products later in the synthesis, can lead to significant losses of yield.
Other methods of reduction are described inter alia in J. Amer. Oil Chem. Soc. 49 (1972) 72, where the reduction of triple bonds to cis double bonds in long-chain conjugated fatty acids is carried out with zinc in boiling protic solvents.
The drastic reduction conditions mentioned here are unsuitable for thermally labile compounds.
Helv. Chim. Acta 58 (1975) 1016 describes the reduction of conjugated alkynes in protic solvents. The reducing agent used by the authors is zinc dust which has been activated by the addition of potassium cyanide.
On the one hand, the abovementioned methods give only moderate yields; on the other hand, the activation with potassium cyanide carries an appreciable health risk.
The paper published in Journal fxc3xcr praktische Chemie 336 (1994) 714-715 contains a method for the (Z)-selective reduction of conjugated triple bonds with a combination of Zn (Cu/Ag) in polar protic solvents, e.g. methanol/water.
This process has the disadvantage that the reagent is very expensive to prepare and moreover must always be freshly prepared.
It is therefore an object of the present invention to provide a process for the partial reduction of alkyne compounds which avoids the abovementioned disadvantages of the prior art.
We have found that this object is achieved by a process for the preparation of cyclohexene derivatives of general formulae I or II: 
in which the substituents R1 and R2 independently of one another are defined as follows:
R1 is 
R2 is OH or a protective group convertible to a hydroxyl group by hydrolysis;
R3 and R4 
are hydrogen or C1-C4-alkyl; and
R5 is hydrogen or C1-C4-acyl,
by the reduction of alkyne compounds of general formulae III or IV: 
in which the substituents R1 and R2 are as defined above, wherein the reducing agent used is a mixture of zinc and at least one compound B selected from the group consisting of ammonium salts, copper salts and alkali metal and alkaline earth metal salts.
Alkyl radicals R3 and R4 which may be mentioned are linear or branched C1-C4-alkyl chains, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl. Preferred alkyl radicals are methyl and ethyl.
The radicals R3 and R4 can also form a cycloheptyl or cyclohexyl ring together with the carbon atom to which they are bonded.
Substituents R5 which may be mentioned are linear or branched C1-C4-acyl chains, e.g. formyl, acetyl, propionyl and isopropionyl. The preferred acyl radical is acetyl.
Suitable protective groups R2 convertible to a hydroxyl group by hydrolysis are functional groups which can be converted to the hydroxyl group relatively easily. Examples which may be mentioned are ether groups such as 
and xe2x80x94Oxe2x80x94C(CH3)3 
silyl ether groups such as xe2x80x94Oxe2x80x94Si(CH3)3, xe2x80x94Oxe2x80x94Si(CH2CH3)3, xe2x80x94Oxe2x80x94Si(isopropyl)3, xe2x80x94Oxe2x80x94Si(CH3)2(tert-butyl) and xe2x80x94Oxe2x80x94Si(CH3)2(n-hexyl), or substituted methyl ether groups such as the xcex1-alkoxyalkyl ether groups of the formulae xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94CH3, 
and suitable pyranyl ether groups such as the tetrahydropyranyloxy group and the 4-methyl-5,6-dihydro-2H-pyranyloxy group.
The group used for R2 is particularly advantageously the tetrahydropyranyloxy group: 
or the xcex1-ethoxyethoxy group of the formula 
Conditions for cleaving the abovementioned protective groups can be found inter alia in T. Greene xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, 1981, Chapter 2.
In one preferred process variant, the reducing agent used is a mixture of zinc and at least one ammonium salt of formula V: 
in which the substituents independently of one another are defined as follows:
R6 to R8 
are hydrogen, C1-C6-alkyl or aryl; and
Yxe2x88x92 is an anion of an organic or inorganic acid.
Alkyl radicals R6 to R8 which may be mentioned are linear or branched C1-C6-alkyl chains, e.g. methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Preferred alkyl radicals are methyl, ethyl, n-propyl and 1-methylethyl.
Hydrogen may be mentioned as the particularly preferred radical for R6 to R8.
Aryl is to be understood as meaning aromatic rings or ring systems having from 6 to 18 carbon atoms in the ring system, for example phenyl or naphthyl, which can optionally be substituted by one or more radicals such as halogen, e.g. fluorine, chlorine or bromine, amino, C1-C4-alkylamino, C1-C4-dialkylamino, hydroxyl, C1-C4-alkyl, C1-C4-alkoxy or other radicals. Optionally substituted phenyl, methoxyphenyl and naphthyl are preferred.
Yxe2x88x92 is generally an anion of an organic or inorganic acid.
Organic acids are to be understood as meaning, inter alia, aliphatic and aromatic carboxylic acids, for example benzoic acid or C1-C12-alkanoic acids, preferably C1-C6-alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid or caproic acid, particularly preferably acetic acid, or dicarboxylic acids such as oxalic acid, malonic acid or succinic acid.
Yxe2x88x92 can also be an anion of an organic sulfonic acid, such as methanesulfonate or para-toluenesulfonate.
Examples of inorganic acids are, inter alia, hydrochloric acid, hydrobromic acid, carbonic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid and phosphoric acid.
The present invention further relates to a process for the preparation of cyclohexene derivatives of formulae I or II wherein the reducing agent used is a mixture of zinc and at least one copper salt selected from the group consisting of copper(I) bromide, copper(I) chloride, copper(II) acetate, copper(II) bromide, copper(II) carbonate, copper(II) chloride, copper(II) nitrate, copper(II) oxalate and copper(II) sulfate. Copper(II) sulfate may be mentioned as the preferred copper salt.
In another embodiment of the process according to the invention, the reducing agent used is a mixture of zinc and at least one alkali metal or alkaline earth metal salt selected from the group consisting of sodium bromide, sodium chloride, sodium acetate, sodium carbonate, sodium hydrogencarbonate, sodium oxalate, sodium sulfate, potassium bromide, potassium chloride, potassium acetate, potassium carbonate, potassium hydrogencarbonate, potassium oxalate, potassium sulfate and the corresponding lithium salts, calcium bromide, calcium chloride, calcium acetate, calcium carbonate, calcium oxalate, calcium sulfate, magnesium bromide, magnesium chloride, magnesium acetate, magnesium carbonate, magnesium oxalate and magnesium sulfate and the corresponding barium salts.
In one particularly preferred process variant, the reducing agent used is a mixture of zinc and at least one ammonium salt of formula V selected from the group consisting of ammonium chloride, ammonium carbonate, ammonium hydrogencarbonate, ammonium sulfate and ammonium acetate. The substituents R6 to R8 are all hydrogen in this case. Ammonium chloride may be mentioned as the very particularly preferred ammonium salt.
The process according to the invention is particularly suitable for the preparation of the cyclohexene compounds of formulae Ia and IIa: 
The general procedure for carrying out the process is to meter an aqueous solution of the compound B into the alkyne compounds of formulae III or IV and then to add the zinc to this mixture, or to meter a suspension of zinc in an aqueous solution of the compound B into the abovementioned alkyne compounds.
However, the converse procedure is also possible, the zinc being suspended in an aqueous solution of the compound B and the alkyne compounds III or IV being added to this suspension.
It has furthermore been found that the reduction according to the invention takes place particularly advantageously in the presence of water.
The amount of water is chosen so that the compound B is dissolved or partially dissolved. Normally 15 to 500 ml of water, preferably 20 to 400 ml and particularly preferably 30 to 250 ml of water are used per mole of zinc.
The addition of an inert solvent has also proved advantageous for the progress of the reduction.
In general, any solvents inert toward the compounds I to IV are suitable as inert solvents in the process according to the invention. The process is preferably carried out in chlorohydrocarbons, e.g. dichloromethane, perchloroethylene or chloroform, or in an ether solvent such as a dialkyl ether, tetrahydrofuran or dioxane, and especially in the water-immiscible methyl tert-butyl ether. Other suitable solvents are aromatic hydrocarbons, especially toluene, and C1-C3-alcohols such as methanol, ethanol or propanol.
It is preferred to use a 10 to 50% by weight solution of the alkynediol in one of the abovementioned solvents, particularly preferably a 15 to 30% by weight solution of the alkynediol in methylene chloride.
In addition to the abovementioned solvents, it is also possible to use acetic acid as a cosolvent.
When using the zinc/copper reducing agent system, said reducing agent is prepared by adding approx. 0.02 mol of the abovementioned copper salts, especially copper sulfate, in aqueous solution per mole of zinc.
The zinc is used in an amount of about 0.5 to 5, preferably 0.7 to 3, particularly preferably 1 to 2 and very particularly preferably 1.2 to 1.6 gram atoms per mole of alkynediol to be reduced. The zinc can be metered in one or more portions.
0.5 to 5 mol, preferably 0.7 to 3 mol and particularly preferably 1 to 2 mol of compound B are used per mole of zinc.
The reduction can be carried out at temperatures between 0xc2x0 C. and the boiling point of the particular solvent. Preferred reaction temperatures range from 10 to 80xc2x0 C. and particularly preferably from 35 to 45xc2x0 C.
The subject of the present invention will be illustrated in greater detail by means of the following examples.